title: Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism.
abstract: Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery.
authors.affiliation: Developmental Biology, MRC-National Institute for Medical Research, London, United Kingdom ; Division of Medicine, University College London, London, United Kingdom.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Breckenridge
authors.forename: Izabela
authors.initials: I
authors.lastname: Piotrowska
authors.forename: Keat-Eng
authors.initials: KE
authors.lastname: Ng
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ragan
authors.forename: James A
authors.initials: JA
authors.lastname: West
authors.forename: Surendra
authors.initials: S
authors.lastname: Kotecha
authors.forename: Norma
authors.initials: N
authors.lastname: Towers
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
authors.forename: Hillary K
authors.initials: HK
authors.lastname: Siddall
authors.forename: John L
authors.initials: JL
authors.lastname: Offer
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yelon
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Jules L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.forename: Alex P
authors.initials: AP
authors.lastname: Gould
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mohun
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D004734:Energy Metabolism / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; C095572:Hand1 protein, mouse; C497443:Hif1a protein, mouse